Macrophage Plasticity in Inflammatory Lung Injury

炎症性肺损伤中的巨噬细胞可塑性

• 批准号: 10170858
• 负责人: Asrar B. Malik
• 金额: $ 228.15万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10170858
• 关键词: Acute Lung Injury; Address; Admission activity; Adult Respiratory Distress Syndrome; Alveolar; Anti-Inflammatory Agents; Automobile Driving; Biology; Bone Marrow; COVID-19 pandemic; CREB1 gene; Cells; Characteristics; Clinical; Complement; Critical Illness; Development; Disease; Endothelial Cells; Endothelium; Environment; Epithelial; Equilibrium; Face; Foundations; Functional disorder; Future; Generations; Genetic; Genetic Transcription; Genomics; Homeostasis; Host Defense; Image; Immune; Immune response; Immune system; Infection; Inflammation; Inflammatory; Injury; Instruction; Intensive Care Units; Intervention; Ion Channel; Lung; Lung Inflammation; Measures; Mediating; Microbe; Mus; Patients; Phagocytosis; Phenotype; Population; Potassium; Process; Purinoceptor; Reporter; Research; Resolution; Role; Sampling; Sentinel; Signal Pathway; Signal Transduction; Structure of parenchyma of lung; Supportive care; Testing; Therapeutic; Tissues; WNT Signaling Pathway; acute care; beta catenin; cytokine; innovation; insight; interstitial; intravital imaging; lung injury; lung repair; macrophage; monocyte; mortality; new therapeutic target; novel; novel strategies; novel therapeutic intervention; optogenetics; pathogen; postnatal; prevent; programs; recruit; repair function; repaired; success; synthetic biology; tissue repair; tool; transcription factor; transcriptomics

RESEARCH SUMMARY/ABSTRACT OF PROGRAM The fundamental challenge in treating the hyper-inflammatory state underlying Acute Lung Injury/Acute Respiratory Distress Disorder (ALI/ARDS) is that broad anti-inflammatory interventions could compromise host defense and potentially exacerbate the underlying infectious process that triggered ALI/ARDS. Novel targeted approaches to treat ALI/ARDS thus require an in-depth understanding of the intricate inflammatory mechanisms to reduce the extent of injury and promote the resolution of inflammation as well as the initiation of lung repair without compromising host defense. It is now recognized that macrophages (Mφ) in lungs represent diverse multi-functional cell populations. They have the ability to sense pathogens and danger signals, and their plasticity and diversity allows them to respond in specialized manners to specific niche environments. They are able to change their phenotypes in a chameleon-like manner by activation of specialized transcriptional programs. Thus, they have the remarkable ability to amplify inflammation and also to coordinate resolution of lung inflammatory lung injury and restore homeostasis. Mφ carry out these functions through the release of an array of cytokines, phagocytosis of microbes, efferocytosis of dead cells, and provide the essential inflammatory or reparative signals to nearby cells. The central focus of this program will be to precisely define the roles of distinct macrophage subpopulations in inflammatory lung injury and signaling nodes to harness the plasticity of macrophages and thereby bring about the resolution of lung injury. Project 1 will test the hypothesis that two specific specific ion channels, P2RX7 (Purinergic Receptor 2 subtype X7) and the potassium (K+) efflux channel TWIK2 regulate the plasticity to either promote lung injury or to activate the repair program. Project 2 will test the hypothesis that the transcription factor CREB and its downstream targets are critical regulators of the anti- inflammatory and reparative function of alveolar Mφ. Project 3 will test the hypothesis that endothelial cells lining all lung vessels direct the plasticity of Mφ via modulation of Wnt signaling in Mφ. Project 4 will test the hypothesis that circulating postnatal CX3CR1+ monocytes replenish lung interstitial Mφ during inflammatory injury and can direct the lung tissue repair program. These four Projects are supported and complemented by highly innovative scientific Cores which will provide important optogenetic tools (Synthetic Biology and Optogenetics Core B), super-resolution and intravital imaging (Advanced Imaging Core C), and access to clinical samples as well as single cell transcriptomic analysis of macrophages (Clinical Sampling and Genomics Core D) to unravel the complexities of macrophage biology in lung injury, thus paving the way for much-needed novel therapeutic approaches in ALI/ARDS.

研究概要/项目摘要 治疗急性肺损伤/急性肺损伤的高炎症状态的根本挑战 呼吸窘迫症 (ALI/ARDS) 是指广泛的抗炎干预措施可能会损害宿主 防御并可能加剧引发 ALI/ARDS 的潜在感染过程。 因此，治疗 ALI/ARDS 的方法需要深入了解复杂的炎症机制 减少损伤程度，促进炎症消退以及肺部修复的启动 现在人们认识到肺中的巨噬细胞（Mφ）代表着不同的细胞。 它们具有感知病原体和危险信号的能力及其可塑性。 多样性使他们能够以专门的方式应对特定的利基环境。 通过激活专门的转录程序以类似变色龙的方式改变它们的表型。 它们具有放大炎症和协调肺部炎症消退的非凡能力 Mφ 通过释放一系列细胞因子来实现这些功能， 微生物的吞噬作用，死细胞的胞吞作用，并提供必要的炎症或修复作用 该计划的中心重点是精确定义不同细胞的作用。 炎症性肺损伤和信号节点中的巨噬细胞亚群利用可塑性 巨噬细胞从而解决肺损伤 项目 1 将检验两个假设。 特定离子通道、P2RX7（嘌呤能受体 2 亚型 X7）和钾 (K+) 外排通道 TWIK2 调节可塑性以促进肺损伤或激活项目 2 将测试的修复程序。 假设转录因子 CREB ​​及其下游靶标是抗- 肺泡 Mφ 的炎症和修复功能 项目 3 将检验内皮细胞衬里的假设。 所有肺血管通过调节 Mφ 中的 Wnt 信号传导来指导 Mφ 的可塑性。项目 4 将测试 Mφ 的可塑性。 假设出生后循环 CX3CR1+ 单核细胞在炎症过程中补充肺间质 Mφ 损伤并可以指导肺组织修复计划 这四个项目得到了支持和补充。 创新的高度科学核心将提供重要的光遗传学工具（合成生物学和 光遗传学核心 B)、超分辨率和活体成像 (高级成像核心 C)，以及访问 临床样本以及巨噬细胞的单细胞转录组分析（临床采样和 基因组学核心 D）揭示肺损伤中巨噬细胞生物学的复杂性，从而为 ALI/ARDS 急需的新型治疗方法。